Congenital heart disease (CHD), the most common significant birth defect, affects 8 per 1000 live births (estimated 30-40,000 children each year). Children with CHD often require surgical interventions. Support techniques integral to cardiac surgery include cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). These procedures may result in detrimental effects in these vulnerable pediatric patients. The early, enthusiastic use of DHCA, particularly in neonates, has been tempered by the finding of significant neurological morbidity associated with its prolonged exposure. Children who had undergone heart surgery with CPB and DHCA as neonates and infants were evaluated after they reached preschool and school age. These children were found to have distinctive patterns of neurological disturbance characterized by cognitive impairment, impaired executive function, expressive speech and language abnormalities, impaired visual-spatial and visual-motor skills, attention deficit/hyperactivity disorder, motor delays, and learning disabilities The neuropathological basis for these disturbances include (i) post-operative periventricular leukomalacia, seen in over 50% of post- operative MRI scans; (ii) post-operative seizures which arise in about 11%; and (iii) stroke, demonstrated in about 9% of post-operative MRIs. It is therefore extremely important to find the conditions which will decrease the neurologic sequelae of CPB and DHCA and protect the brain from injury. Further progress in the improvement of therapeutic and preventive strategies with respect to cerebral injury during cardiac bypass depends on increased understanding of how DHCA affects the critical cellular neuropathologic processes that lead to cell death. This research will continue to study the mechanisms responsible for DHCA-dependent neuronal injury and determine the efficacy of neuroprotection by two promising compounds, GCSF and topiramate, and of hypothermia during post-bypass recovery. In this series of experiments, we will characterize the brain injury patterns with commonly used clinical DHCA and CPB strategies, and extend the potential for neuroprotection by studying emerging neuroprotective stategies (hypothermia 32-34C) and clinically applicable agents (GCSF, topiramate), alone or in combination. We will discover how the timing, intensity, and duration of neuroprotective exposure affects vulnerable neonatal brain injury and the activation of cell injury and death processes. These findings will help define the contributions of selected mechanisms by which hypoxic- ischemic brain injury induced by DHCA, CPB and reperfusion is likely to occur, as well as evaluate clinically applicable neuroprotective strategies that have the potential to significantly improve neurologic outcomes for infants and children. PUBLIC HEALTH RELEVANCE: Newborns who survive heart surgery face a variety of neurological deficits, including global cognitive dysfunction, visual-spatial disorders, impaired fine and gross motor control, impaired executive/planning function and attention deficit hyperactivity disorder. This research will determine the mechanisms brain injury by the surgical procedures, and critically evaluate mild hypothermia as well as two promising protective agents, Granulocyte Colony-Stimulating Factor (GCSF) and Topiramate both alone and together, for their efficacy in protecting the brain from injury resulting from the surgery.